In asthma and chronic obstructive pulmonary disease (COPD), active human airway smooth muscle (HASM) cellular contraction limits airflow, representing a major cause of morbidity and mortality. β2-adrenergic receptors (β2Ars), expressed on HASM cells, have been conventionally targeted by administering unbiased β-agonists, that stabilize conformation(s) that evoke coupling to Gαs and β-arrestin engagement. These agonists have been associated with tachyphylaxis, an attenuated response due to receptor desensitization, with typical treatments of humans, or HASM cells, leading to a loss of receptor function over time.
USF researchers screened a 40-million-compound scaffold ranking library to identify compounds that are Gαs-promoting agonists (lead to airway relaxation) but biased away from β-arrestin engagement (limit effectiveness due to receptor desensitization), which should improve airway response with reduced tachyphylaxis. Of several agonists identified, one compound (C1-S) was particularly notable for the apparent absence of β-arrestin engagement while displaying Gαs coupling to cAMP production as well as airway smooth muscle relaxation. Agonist receptor-G protein modeling revealed different receptor interactions compared to other agonists. The favorable effects of the apparent biasing with this agonist were demonstrated in a physiologic system (ASM relaxation). These studies point to a different structural class of β agonists that might be used to treat obstructive lung diseases without the adverse effects associated with tachyphylaxis.
Dose-response curve of cAMP production in nontransfected Chinese hamster fibroblast (CHW) cells and in CHW-β2 cells after treatment with C1-S.